Modified release doxycycline composition

ABSTRACT

Doxycycline formulations with a reduced food effect are disclosed. Particularly disclosed are modified release formulations which can be administered once a day and exhibit a reduced food effect. Methods of treating inflammatory conductions such as rosacea or inflammatory symptoms such as the papules and pustules of rosacea or acne vulgaris are also disclosed.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a Continuation Application of U.S. patentapplication Ser. No. 16/388,415, filed Apr. 18, 2019, which is aDivisional Application of U.S. patent application Ser. No. 15/875,369,filed Jan. 19, 2018, now U.S. Pat. No. 10,300,081, which is aContinuation Application of U.S. patent application Ser. No. 15/359,292,filed Nov. 22, 2016, now U.S. Pat. No. 9,901,588, which is aContinuation Application of U.S. patent application Ser. No. 14/946,715,filed Nov. 19, 2015, now U.S. Pat. No. 9,532,996, which claims thebenefit of the filing date of Indian Patent Application No. IN5805/CHE/2014, filed Nov. 19, 2014, the disclosures of which are herebyincorporated herein by reference.

FIELD OF INVENTION

The present application relates to a modified release composition ofdoxycycline.

BACKGROUND

Doxycycline is a broad spectrum bacteriostatic compound that iseffective against Gram-positive, Gram-negative, aerobic and anaerobicbacteria, as well as spirochetes, mycoplasmas, rickettsiae, chlamydiaeand some protozoans. It works by inhibiting protein synthesis inbacteria or protozoans. It is commonly used in the treatment ofbacterial infections caused by these organisms, such as urinary tractinfections, upper respiratory tract infections, acne, gonorrhea,chlamydia, anthrax, lyme disease and others.

Besides antibiotic activity, doxycycline also has some other mechanismof actions like interfering with the chemotaxis of polymorphonuclearleukocytes (PMN) into the inflammatory lesion, inhibition of PMN derivedcollagenase, scavenging reactive oxidative species produced by residentinflammatory cells etc. Therefore doxycycline is also being used as ananti-inflammatory to treat inflammatory conditions or symptoms, such asdiseases like periodontitis, rosacea and acne. In these instances, it isused in an anti-inflammatory effective amount which, may be lower thantraditionally prescribed when doxycycline is used for its antibioticactivity.

Doxycycline as an antibiotic is available in 50 mg, 100 mg, and 200 mgoral doses, whereas as for treating periodontitis and rosacea, lowerstrengths of 20 mg & 40 mg oral doses are marketed as PERIOSTAT® andORACEA® respectively. These doses can be given once or more per day asdirected by a physician. ORACEA® is a 40 mg dose administered once in a24 hour period. Sustained release formulations of doxycycline are alsodescribed in U.S. Pat. Nos. 5,084,287 and 5,188,836.

Oral administration of drugs is frequently affected by food-druginteractions, a phenomenon often described by the term “food effect”.Food effect generally refers to all type of interactions of food withdrug which affect its dissolution, absorption, distribution, metabolismand/or elimination. The implications of food effect can, in someinstances, include changes in bioavailability, rate of on-set oftherapeutic action, duration of therapeutic effect and incidence of sideeffects.

The food effect is an important issue during the development of a drug.In some cases food-drug interactions lead to an increase of drugabsorption and the drug formulation may be recommended to be taken withfood in order to be sufficiently absorbed and exert its expectedclinical effect. In some other case food interrupts the absorption ofactive agent and therefore it reduces C_(max) and AUC leading to poortherapeutic effect. In those cases, there may be warnings provided tothe user to take the drug, for example, one hour before or two hoursafter eating.

The food effect on doxycycline pharmacokinetics is well known. Indeed,ORACEA® is reported to have 45% and 22% in C_(max) and AUC respectively(meaning that the C_(max) and AUC of ORACEA® when given in the fedversus fasted state differ by 45% and 22% respectively) and carries theexact dosing restriction noted above.

In addition to its known impact on the gastrointestinal microbiology ofa patient, doxycycline is known to have possible adverse gastrologicaleffects which are attributed to irritation of the mucosa. Such effectsmay include anorexia, nausea, diarrhoea, glossitis, dysphagia,enterocolitis. Further there is huge risk of esophageal irritation andulceration in patients receiving capsule and tablet forms of thedoxycycline, especially when patients immediately go to bed or lie downfollowing dosing, or when the doses are taken without sufficient liquid.Therefore it is necessary the patients should be administered withadequate amounts of fluid or food and the patients are instructed toremain sitting or standing for up to 2 hours post administration toprevent the possible development of oesophageal irritation. Similarrestrictions are known for other drug products, like bisphosphonates.These dosing restrictions can understandably cause inconvenience anddiscomfort to the patients which can impact compliance.

Thus, a need exists to provide a modified release dosage form ofdoxycycline with reduced or no significant food effect. Further it isdesired to have a dosage form of doxycycline which are expected toreduce or prevent risk of esophageal irritation and ulceration inpatients and further improves the compliance.

SUMMARY OF THE INVENTION

The present application relates to a modified release composition ofdoxycycline.

In one embodiment, the present application relates to a modified releasecomposition comprising:

-   -   I. doxycycline;    -   II. one or more water soluble and insoluble polymers; and    -   III. one or more pharmaceutically acceptable excipients;    -   wherein said composition when subjected to a changeover        dissolution study releases no more than 30% in 30 minutes, in        750 ml of pH 1.2 acidic solution (0.1N HCl); and has at least        one of the following release profile in 950 ml of an pH 6.0        phosphate buffer solution:    -   a. less than about 30% in 35 minutes;    -   b. less than about 60% in 45 minutes; and    -   c. more than 85% in 60 minutes

In another embodiment, the modified release composition of the presentapplication comprising doxycycline, wherein said composition provides atleast one of the following pharmacokinetic parameters:

-   -   a. doxycycline plasma concentration of not more than about 50        ng/ml of doxycycline at 30 minutes;    -   b. doxycycline plasma concentration of not more than about 100        ng/ml of doxycycline at 45 minutes; and    -   c. doxycycline plasma concentration of not more than about 200        ng/ml of doxycycline at 60 minutes.

In another embodiment, the modified release composition of the presentapplication provides peak plasma concentration from about 200 ng/ml toabout 1000 ng/ml of doxycycline at 90 minutes.

In another embodiment, the modified release composition of the presentapplication comprising doxycycline provides at least one of thefollowing pharmacokinetic parameters:

-   -   a. doxycycline plasma concentration of not more than about 15        ng/ml of doxycycline at 30 minutes;    -   b. doxycycline plasma concentration of not more than about 60        ng/ml of doxycycline at 45 minutes; and    -   c. doxycycline plasma concentration of not more than about 200        ng/ml of doxycycline at 60 minutes.

In another embodiment, the present application relates to a modifiedrelease composition for once daily oral administration comprising:

-   -   I. doxycycline,    -   II. one or more water soluble and insoluble polymers and    -   III. one or more pharmaceutically acceptable excipients,    -   wherein said composition upon oral administration to a human        subjects in fasting state provides at least one of the        doxycycline plasma concentration parameters:    -   a. not more than about 15 ng/ml of doxycycline at 30 minutes;    -   b. not more than about 60 ng/ml of doxycycline at 45 minutes;        and    -   c. not more than about 200 ng/ml of doxycycline at 60 minutes.

In another embodiment, the present application relates to a modifiedrelease composition comprising:

-   -   I. doxycycline;    -   II. one or more water soluble and insoluble polymers; and    -   III. one or more pharmaceutically acceptable excipients;    -   wherein said composition upon oral administration in fasting        state exhibits bioequivalence to a commercially available 40 mg        doxycycline composition and said bioequivalence is established        by:    -   a. a 90% Confidence Interval for mean AUC_((0-t)), which is        between 80% and 125%,    -   b. a 90% Confidence Interval for mean AUC_((0-inf)), which is        between 80% and 125%, and    -   c. a 90% Confidence Interval for mean C_(max), which is between        80% and 125%.

In another embodiment, the present application relates to a modifiedrelease composition comprising:

-   -   I. doxycycline,    -   II. one or more water soluble and insoluble polymers and    -   III. one or more pharmaceutically acceptable excipients,    -   wherein said composition upon oral administration in a fed state        exhibits bioequivalence to a commercially available 40 mg        doxycycline composition administered in fasting state and said        bioequivalence is established by:    -   a. a 90% Confidence Interval for mean AUC_((0-t)), which is        between 80% and 125%; and    -   b. a 90% Confidence Interval for mean AUC_((0-inf)), which is        between 80% and 125%.        In another aspect of this embodiment the composition is provided        as a once a day oral dosage form.

In another embodiment, the present application relates to a modifiedrelease composition comprising:

-   -   I. doxycycline;    -   II. one or more water soluble and insoluble polymers; and    -   III. one or more pharmaceutically acceptable excipients;    -   wherein said composition provides at least one of the following        pharmacokinetic parameters:    -   a) a fed/fasted ratio for C_(max) in the range of about 0.60 to        about 1.00;    -   b) a fed/fasted ratio for AUC_(0-t) in the range of about 0.89        to about 1.00; and    -   c) a fed/fasted ratio for AUC_(0-inf) in the range of about 0.89        to about 1.00.

In another embodiment, the present application relates to a method oftreating rosacea in a human subject in need thereof comprising:

-   -   I. doxycycline,    -   II. one or more water soluble and insoluble polymers, and    -   III. one or more pharmaceutically acceptable excipients;    -   wherein said composition has reduced food effect.

In another embodiment, the present application relates to a method oftreating rosacea or an inflammatory symptom of rosacea or acne vulgarisin a human subject in need thereof comprising:

-   -   I. doxycycline,    -   II. one or more water soluble and insoluble polymers and    -   III. one or more pharmaceutically acceptable excipients,    -   wherein said composition upon oral administration in a fed state        exhibits bioequivalence to a commercially available 40 mg        doxycycline composition administered in fasting state and said        bioequivalence is established by:    -   a. a 90% Confidence Interval for mean AUC_((0-t)), which is        between 80% and 125%; and    -   b. a 90% Confidence Interval for mean AUC_((0-inf)), which is        between 80% and 125%.

In another embodiment, the method of treating rosacea or an inflammatorysymptom of rosacea or acne vulgaris in a human subject in need thereofcomprising orally administering a modified release composition ofdoxycycline, wherein said composition has reduced food effect.

In another embodiment, the method of treating rosacea or an inflammatorysymptom of acne vulgaris in a human subject in need thereof comprisingorally administering a modified release composition of doxycycline,wherein said composition has reduced food effect, and said food effectis less than about 40% in C_(max)

In another embodiment, the method of treating rosacea or an inflammatorysymptom of rosacea or acne vulgaris in a human subject in need thereofcomprising orally administering a modified release composition ofdoxycycline, wherein said composition has reduced food effect, and saidfood effect is less than about 35% in C_(max)

In another embodiment, the method of treating rosacea or an inflammatorysymptom of rosacea or acne vulgaris in a human subject in need thereofcomprising orally administering a modified release composition ofdoxycycline, wherein said composition has reduced food effect, and saidfood effect is less than about 15% in AUC (AUC_((0-t)) and/orAUC_((0-inf))).

In another embodiment, the method of treating rosacea or an inflammatorysymptom of rosacea or acne vulgaris in a human subject in need thereofcomprising orally administering a modified release composition ofdoxycycline, wherein said composition has reduced food effect, and saidfood effect is less than about 12% in AUC (AUC_((0-t)) and/orAUC_((0-inf)).

In another embodiment, the method of treating rosacea or an inflammatorysymptom of rosacea or acne vulgaris in a human subject in need thereofcomprising orally administering an once daily modified releasecomposition comprising doxycycline, wherein said composition has reducedfood effect and said food effect is lower than the food effect ofcommercially available 40 mg doxycycline composition by at least 15% inC_(max) and AUC (AUC_((0-t)) and/or AUC_((0-inf)))

In another embodiment, the method of treating rosacea or an inflammatorysymptom of rosacea or acne vulgaris in a human subject in need thereofcomprising orally administering a modified release compositioncomprising:

-   -   I. doxycycline    -   II. one or more water soluble and insoluble polymers; and    -   III. one or more pharmaceutically acceptable excipients;    -   wherein said composition provides at least one of the following        pharmacokinetic parameters:    -   a) a fed/fasted ratio for C_(max) in the range of about 0.60 to        about 1.00;    -   b) a fed/fasted ratio for AUC_(0-t) in the range of about 0.89        to about 1.00; and    -   c) a fed/fasted ratio for AUC_(0-inf) in the range of about 0.89        to about 1.00.

In another embodiment, the method of treating rosacea or an inflammatorysymptom of rosacea or acne vulgaris in a human subject in need thereofcomprising orally administering a modified release compositioncomprising:

-   -   I. doxycycline;    -   II. one or more water soluble and insoluble polymers; and    -   III. one or more pharmaceutically acceptable excipients;    -   wherein said composition upon oral administration in fasting        state exhibits bioequivalence to a commercially available 40 mg        doxycycline composition and said bioequivalence is established        by:    -   a. a 90% Confidence Interval for mean AUC_((0-t)), which is        between 80% and 125%,    -   b. a 90% Confidence Interval for mean AUC_((0-inf)), which is        between 80% and 125%, and    -   c. a 90% Confidence Interval for mean C_(max), which is between        80% and 125%.

In another embodiment, the method of treating rosacea or an inflammatorysymptom of rosacea or acne vulgaris in a human subject in need thereofcomprising orally administering a modified release compositioncomprising:

-   -   I. about 46 mg of doxycycline hyclate;    -   II. one or more water soluble and insoluble polymers; and    -   III. one or more pharmaceutically acceptable excipients;    -   wherein said composition upon oral administration in fasting        state exhibits bioequivalence to a commercially available 40 mg        doxycycline composition and said bioequivalence is established        by:

d. a 90% Confidence Interval for mean AUC_((0-t)), which is between 80%and 125%,

-   -   e. a 90% Confidence Interval for mean AUC_((0-inf)), which is        between 80% and 125%, and    -   f. a 90% Confidence Interval for mean C_(max), which is between        80% and 125%.

In another embodiment, the present application relates to a modifiedrelease composition comprising

-   -   I. doxycycline;    -   II. one or more water soluble and insoluble polymers; and    -   III. one or more pharmaceutically acceptable excipients;    -   wherein said composition has dC/dT value less than about 80% of        the dC/dT value provided by the commercially available 40 mg        doxycycline composition, and said dC/dT value is measured in a        single dose human pharmacokinetic study in a fasting state and        for a time period of T_(0min) to T_(60mins).

In another embodiment, the modified release composition of the presentapplication comprising

-   -   I. doxycycline    -   II. one or more water soluble and insoluble polymers; and    -   III. one or more pharmaceutically acceptable excipients;    -   wherein said composition has dC/dTvalue less than about 80% of        the dC/dT value provided by the commercially available 40 mg        doxycycline composition, and said dC/dT value is measured in a        single dose human pharmacokinetic study in a fasting state and        in a time period of T_(0min) to T_(60min), wherein said        composition provides at least one of the following        pharmacokinetic parameters:    -   a. average input rate of from about 4 ng/hr/ml to about 15        ng/hr/ml during the time period of T_(0min) to T_(30mins).    -   b. average input rate of from about 15 ng/hr/ml to about 40        ng/hr/ml during the time period of T_(0min) to T_(60mins).

In another embodiment, the modified release composition of the presentapplication comprising

-   -   I. doxycycline;    -   II. one or more water soluble and insoluble polymers; and    -   III. one or more pharmaceutically acceptable excipients;    -   wherein said composition has dC/dTvalue less than about 80% of        the dC/dT value provided by the commercially available 40 mg        doxycycline composition, and said dC/dT value is measured in a        single dose human pharmacokinetic study in a fasting state and        in a time period of T_(0min) to T_(60min), wherein said        composition provides at least one of the following        pharmacokinetic parameters:    -   a. average input rate of from about 5 ng/hr/ml to about 8        ng/hr/ml during the time period of T_(0min) to T_(30mins).    -   b. average input rate of from about 15 ng/hr/ml to about 20        ng/hr/ml during the time period of T_(0min) to T_(60mins).

In another embodiment, the modified release composition comprising

-   -   I. doxycycline;    -   II. one or more water soluble and insoluble polymers; and    -   III. one or more pharmaceutically acceptable excipients;    -   wherein said composition has dC/dT value less than about 80% of        the dC/dT value provided by the commercially available 40 mg        doxycycline composition, and said dC/dT value is measured in a        single dose human pharmacokinetic study in a fasting state and        in a time period of T_(0min) to T_(60min), wherein said        composition has reduced food effect.

In another embodiment, the modified release composition comprisingdoxycycline has reduced food effect, and said food effect is less thanabout 40% in C_(max).

In another embodiment, the modified release composition of the presentapplication has reduced food effect, and said food effect is less thanabout 35% in C_(max).

In another embodiment, the modified release composition comprisingdoxycycline has reduced food effect, and said food effect is less thanabout 15% in AUC_((0-t)).

In another embodiment, the modified release composition comprisingdoxycycline has reduced food effect, and said food effect is less thanabout 12% in AUC_((0-t)).

In another embodiment, the modified release composition comprisingdoxycycline has reduced food effect, and said food effect is less thanabout 15% in AUC_((0-inf)).

In another embodiment, the modified release composition comprisingdoxycycline has reduced food effect, and said food effect is less thanabout 12% in AUC_((0-inf)).

In another embodiment, the modified release composition comprising

-   -   I. doxycycline;    -   II. one or more water soluble and insoluble polymers; and    -   III. one or more pharmaceutically acceptable excipients;    -   wherein said composition has dC/dT value less than about 80% of        the dC/dT value provided by the commercially available 40 mg        doxycycline composition, and said dC/dT value is measured in a        single dose human pharmacokinetic study in a fasting state and        in a time period of T_(0min) to T_(60min); and    -   wherein said composition has reduced food effect and said food        effect is lower than the food effect of commercially available        40 mg doxycycline composition by at least 15% in C_(max) and AUC        (AUC_((0-t)) and/or AUC_((0-inf)).

In another embodiment, the modified release composition comprising

-   -   I. doxycycline;    -   II. one or more water soluble and insoluble polymers; and    -   III. one or more pharmaceutically acceptable excipients;    -   wherein said composition has dC/dT value less than about 80% of        the dC/dT value provided by the commercially available 40 mg        doxycycline composition, and said dC/dT value is measured in a        single dose human pharmacokinetic study in a fasting state and        in a time period of T_(0min) to T_(60mins); and    -   wherein said composition provides at least one of the following        pharmacokinetic parameters:    -   a) a fed/fasted ratio for C_(max) in the range of about 0.60 to        about 1.00;    -   b) a fed/fasted ratio for AUC_(0-t) in the range of about 0.89        to about 1.00; and    -   c) a fed/fasted ratio for AUC_(0-inf) in the range of about 0.89        to about 1.00.

In another embodiment, the modified release composition comprising

-   -   I. doxycycline;    -   II. one or more water soluble and insoluble polymers; and    -   III. one or more pharmaceutically acceptable excipients;    -   wherein said composition has dC/dT value less than 80% of the        dC/dT value provided by the commercially available 40 mg        doxycycline composition, and said dC/dT value is measured in a        single dose human pharmacokinetic study in a fasting state and        in a time period of T_(0min) to T_(60mins); and    -   wherein said composition upon oral administration in fasting        state exhibits bioequivalence to a commercially available 40 mg        doxycycline composition and said bioequivalence is established        by:    -   a. a 90% Confidence Interval for mean AUC_((0-t)), which is        between 80% and 125%,    -   b. a 90% Confidence Interval for mean AUC_((0-inf)), which is        between 80% and 125%, and    -   c. a 90% Confidence Interval for mean C_(max), which is between        80% and 125%.

In another embodiment, the modified release composition of the presentapplication is orally administered once daily.

In another embodiment, the modified release composition of the presentapplication is orally administered twice daily.

In another embodiment, the modified release composition of the presentapplication is orally administered to human subjects in need thereof.

In another embodiment, the modified release composition of the presentapplication comprises doxycycline, wherein said doxycyline is an acidaddition salt of doxycycline. In still another aspect of thisembodiment, the doxycycline is administered in an amount of betweenabout 30 and less than 50 mg, based on the weight of doxycycline base,in yet another aspect, between about 35 and about 45 mg, and in yet afurther aspect between about 35 and about 40 mg of doxycycline based onthe equivalent weight of doxycycline base.

In another embodiment, the modified release composition of the presentapplication comprises doxycycline, which is doxycycline hyclate.

In another embodiment, doxycycline hyclate is present in an amount ofabout 46 mg.

In another embodiment, doxycycline hyclate is present in an amount of46.16 mg.

In another embodiment there is provided a method of treatinginflammatory rosacea or an inflammatory symptom of either rosacea oracne vulgaris in a human patient in need thereof comprising:administering to said patient a total daily dose of about 35 mg to about45 mg of a doxycycline hydrate or acid addition salt, based on theequivalent weight of doxycycline base, wherein the total daily dose ofdoxycycline is provided so as to result in a reduced food effect.

In another aspect of this method the total daily dose is administeredonce a day and provides a reduced food effect whereby both AUC and aC_(max) are lower than the food effect of commerically available 40 mgdoxycycline compositions by at least about 15%.

In another aspect of the method, the total daily dose is administeredonce a day less than one hour before or less than two hours after ameal.

In another aspect of the method, the total daily dose exhibits a reducedfood effect selected from the group consisting of an AUC of less thanabout 15% and a C_(max) of less than about 40% upon oral administrationto a human in a fed state.

In another aspect of the method, upon oral administration in a fastingstate the total daily dose exhibits bioequivalence to a commerciallyavailable 40 mg doxycycline composition.

In another aspect of the method, bioequivalence is established by:

-   -   a. a 90% Confidence Interval for mean AUC_((0-t)), which is        between 80% and 125%,    -   b. a 90% Confidence Interval for mean AUC_((0-∞)), which is        between 80% and 125%, and    -   c. a 90% Confidence Interval for mean C_(max), which is between        80% and 125%.

In another aspect of the method, the acid addition salt is doxycyclinehyclate is present in an amount of about 46 mg.

In another aspect of the method, the doxycycline is a hydrate and thehydrate is the monohydrate.

In another aspect of the method, the inflammatory symptom of eitherrosacea or acne vulgaris is papules and pustules of either rosacea oracne vulgaris.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows in vitro release profile of Example 1, 2, 3 and ORACEA® inchange over media (Acidic medium-pH1.2 and phosphate buffer-pH 6.0).

FIG. 2 shows in vitro release profile of Example 3 and ORACEA® inacetate buffer −pH 4.5.

FIG. 3 A. shows 12-hour Mean plasma doxycycline concentration −Timeprofile of Example 3 administered to 52 subjects in fasting state.

FIG. 3 B. shows 72-hour Mean plasma doxycycline concentration −Timeprofile of Example 3 administered to 52 subjects in fasting state.

DETAILED DESCRIPTION Definitions

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art.

“Doxycycline” herein refers to any form of doxycycline includinghydrates such as doxycycline monohydrate, anhydrous doxycycline,doxycycline base or acid addition salts of doxycycline such asdoxycycline hyclate or any other pharmaceutically acceptable saltthereof in an amount of about 30 mg to less than 50 mg of doxycyclinebase or an equivalent amount of any other form of doxycycline.

In the present application, the amount of doxycycline used may be fromabout 30 mg to about 45 mg, or from about 35 mg to about 45 mg, or fromabout 35 mg to about 40 mg, or from about 40 mg to about 45 mg ofdoxycycline base or an equivalent amount of any other form ofdoxycycline. For example in the present application, the doxycyclinehyclate in an amount of about 46 mg provides about 40 mg of doxycyclinebase similarly, where it is stated that an amount of or range of one ormore forms of doxycycline is “based on the equivalent weight ofdoxycycline base” or variances thereof, it is meant that the amount ofthat form or forms of doxycycline will be sufficient to provide anequivalent amount of doxycycline base. Thus, for example, about 35 mg toabout 45 mg of doxycycline monohydrate based on the equivalent weight ofdoxycycline base means enough doxycycline monohydrate so as to provide35 to 45 mg of doxycycline base. Unless stated otherwise, these dosesare the total daily dose. They can be given in a single dosage form ormultiple dosage forms, preferably in a single dosage form given once aday.

The amount of doxycycline in certain embodiments thereof is an amountsufficient to provide peak plasma concentration of doxycycline fromabout 200 ng/ml to about 1000 ng/ml. The amount of doxycycline per unitdosage form used in certain embodiments hereof is an amount sufficientto provide an equivalent of about 30 mg to about 40 mg of doxycyclinebase per dose per day or that provides peak plasma concentration ofdoxycycline from about 200 ng/ml to about 1000 ng/ml.

Doxycycline as used herein also encompasses their complexes, polymorphs,hydrates, solvates, enantiomers or racemates. The solid state ofdoxycycline used in the composition of the present application is notcritical. For example, doxycycline can be amorphous or crystalline.

The term “about”, as used herein, means within 10% of a given value orrange. Alternatively, the term “about” means within an acceptablestandard error of the mean as would be appropriate.

The term “food effect”, as used herein, refers to relative difference inAUC (area under the curve AUC_((0-t)) and/or AUC_((0-∞)),) or C_(max)(maximum plasma concentration or peak plasma concentration) of an activesubstance, when said substance or a composition thereof, such as atablet or a capsule, is administered orally to a subject, concomitantlywith food or in a fed state as compared to the same values when the samesubstance or a composition thereof is administered in a fasted state.

-   -   The food effect F is calculated as

${F\mspace{14mu}\%} = {\frac{\left( {X_{fasted} - X_{fed}} \right)}{X_{fasted}} \times 100}$

-   -   wherein X_(fed) and X_(fasted) are the values of AUC        (AUC_((0-t)) and/or AUC_((0-∞))) or C_(max) in the fed and        fasted state, respectively.

The term “reduced food effect”, as used herein, refers to the foodeffect in AUC (AUC_((0-t)) and/or AUC_((0-∞))) and C_(max) of acomposition of doxycycline is less than about 15% and 40% respectively.In C_(max), “reduced food effect” refers to food effect in C_(max) of acomposition of doxycycline and is at least less than about 40%. In AUC,“reduced food effect” refers to food effect in AUC (AUC_((0-t)) and/orAUC_((0-∞))) of a composition of doxycycline and is at least less thanabout 15%. In another embodiment, the reduced food effect is less thanabout 35% in terms of C_(max) or less than about 12% in terms of AUC. Instill another embodiment both AUC and C_(max) are lower than the foodeffect of commerically available 40 mg doxycycline compositions asdefined herein by at least about 15%.

Indeed, because of the reduced food effect of the present inventionparticularly when compared to commercial products such as ORACEA®, it ispossible to administer doxycycline to treat inflammatory conditions orsymptoms of inflammatory conditions (for example, the papules andpustuals of acne vulgaris or rosacea) with a reduced food effect. Insome embodiments this may be accomplished without need for normaladministration warnings and/or without requiring the patient be in afasted state. Because of this, the patient may take their doxycyclinedose even less than an hour before a meal, or two hours after a meal orotherwise in the fed state.

The term “dC/dT” as used herein, refers to change in doxycyclineconcentration in plasma as a function of time or change in plasmaconcentration of doxycycline during the said time period or interval.

-   -   It is calculated as

${{dC}\text{/}{dT}} = \frac{\left( {{{Plasma}\mspace{14mu}{Concentration}_{T\; 2}} - {{Plasma}\mspace{14mu}{Concentration}_{T\; 1}}} \right)}{\left( {{{Time}\mspace{14mu}{point}_{2}} - {{Time}\mspace{14mu}{point}_{1}}} \right)}$

The term “modified release composition” herein refers to any compositionor dosage form which comprises an active drug and which is formulated toprovide a longer duration of pharmacological response afteradministration of the dosage form than is ordinarily experienced afteradministration of a corresponding immediate release compositioncomprising the same drug in the same amount. Modified releasecompositions include, inter alia, those compositions described elsewhereas “controlled release”, “extended release”, “delayed release”,“sustained release”, “prolonged release”, “programmed release”, “timerelease” and/or “rate controlled” compositions or dosage forms.

As used herein, the terms “composition” and “formulation” are usedinterchangeably and refer to a mixture of two or more compounds,elements, or molecules. Also the terms “composition” and “formulation”may be used to refer to a mixture of one or more active agents with acarrier or other excipients. Furthermore, the term “dosage form” caninclude one or more composition(s) or formulation(s) provided in aformat for administration to a patient in need thereof.

The term “Changeover dissolution study” herein refers to a dissolutionstudy performed by using USP apparatus I (Basket) with 50 rpm and thedissolution methodology includes two stages i.e., acid stage followed bybuffer stage. Firstly in vitro dissolution was carried out in acid stagepH 1.2 (750 ml of 0.1N HCl solution, USP Type 1 apparatus at a speed of50 rpm and 37° C.) till 30 minutes and after 30 minutes the study wascontinued in buffer stage (950 ml of phosphate buffer solution (pH 6.0),USP Type 1 apparatus at a speed of 50 rpm and 37° C.). As used herein,the term “commercially available 40 mg doxycycline composition” refersto ORACEA® oral capsules containing doxycycline, USP in an amountequivalent to 40 mg of anhydrous doxycycline, marketed by GaldermaLaboratories, L.P

FURTHER EMBODIMENTS

The present application relates to a modified release compositiondoxycycline.

In another embodiment, the present application relates to a modifiedrelease composition comprising:

-   -   I. doxycycline;    -   II. one or more water soluble and insoluble polymers; and    -   III. one or more pharmaceutically acceptable excipients;    -   wherein said composition when subjected to a changeover        dissolution study releases no more than 20% in 30 minutes, in        750 ml of pH 1.2 acidic solution (0.1N HCl); and have at least        one of the following release profile in 950 ml of an pH 6.0        phosphate buffer solution:    -   a. less than about 30% in 35 minutes;    -   b. less than about 60% in 45 minutes; and    -   c. more than 85% in 60 minutes.

In another embodiment, the present application relates to a modifiedrelease composition comprising:

-   -   I. doxycycline;    -   II. one or more water soluble and insoluble polymers; and    -   III. one or more pharmaceutically acceptable excipients;        wherein said composition when subjected to a changeover        dissolution study releases no more than 10% in 30 minutes, in        750 ml of pH 1.2 acidic solution (0.1N HCl); and have at least        one of the following release profile in 950 ml of an pH 6.0        phosphate buffer solution:    -   a. less than about 30% in 35 minutes;    -   b. less than about 60% in 45 minutes; and    -   c. more than 85% in 60 minutes.

In another embodiment, the present application relates to a modifiedrelease composition comprising:

-   -   I. about 46 mg of doxycycline hyclate;    -   II. one or more water soluble and insoluble polymers; and    -   III. one or more pharmaceutically acceptable excipients;    -   wherein said composition when subjected to a changeover        dissolution study releases no more than 30% in 30 minutes, in        750 ml of pH 1.2 acidic solution (0.1N HCl); and have at least        one of the following release profile in 950 ml of an pH 6.0        phosphate buffer solution:    -   a. less than about 30% in 35 minutes;    -   b. less than about 60% in 45 minutes; and    -   c. more than 85% in 60 minutes.

In another embodiment, the present application relates to a modifiedrelease composition comprising:

-   -   I. about 46 mg of doxycycline hyclate;    -   II. one or more water soluble and insoluble polymers; and    -   III. one or more pharmaceutically acceptable excipients;    -   wherein said composition when subjected to a changeover        dissolution study releases no more than 30% in 30 minutes, in        750 ml of pH 1.2 acidic solution (0.1N HCl); and have at least        one of the following release profile in 950 ml of an pH 6.0        phosphate buffer solution:    -   d. less than about 30% in 35 minutes;    -   e. less than about 60% in 45 minutes;    -   f. more than 85% in 60 minutes;    -   and wherein said composition upon oral administration to a human        subjects in fasting state provides at least one of the following        pharmacokinetic parameters:    -   a. doxycycline plasma concentration of not more than about 15        ng/ml of doxycycline at 30 minutes;    -   b. doxycycline plasma concentration of not more than about 60        ng/ml of doxycycline at 45 minutes;    -   c. doxycycline plasma concentration of not more than about 200        ng/ml of doxycycline at 60 minutes; and    -   d. doxycycline plasma concentration from about 200 ng/ml to        about 1000 ng/ml of doxycycline at above 90 minutes.

In another embodiment, the present application relates to a modifiedrelease composition comprising:

-   -   I. about 46 mg of doxycycline hyclate;    -   II. one or more water soluble and insoluble polymers; and    -   III. one or more pharmaceutically acceptable excipients;    -   wherein said composition when subjected to a changeover        dissolution study releases no more than 30% in 30 minutes, in        750 ml of pH 1.2 acidic solution (0.1N HCl); and have at least        one of the following release profile in 950 ml of an pH 6.0        phosphate buffer solution:    -   (a) less than about 30% in 35 minutes;    -   (b) less than about 60% in 45 minutes; and    -   (c) more than 85% in 60 minutes;    -   and wherein said composition upon oral administration in fasting        state exhibits bioequivalence to a commercially available 40 mg        doxycycline composition administered in fasting state and said        bioequivalence is established by:    -   a. a 90% Confidence Interval for mean AUC_((0-t)), which is        between 80% and 125%,    -   b. a 90% Confidence Interval for mean AUC_((0-inf)), which is        between 80% and 125%, and    -   c. a 90% Confidence Interval for mean C_(max), which is between        80% and 125%.

In another embodiment, the present application relates to a modifiedrelease composition comprising:

-   -   I. about 46 mg of doxycycline hyclate;    -   II. one or more water soluble and insoluble polymers; and    -   III. one or more pharmaceutically acceptable excipients;    -   wherein said composition when subjected to a changeover        dissolution study releases no more than 30% in 30 minutes, in        750 ml of pH 1.2 acidic solution (0.1N HCl); and have at least        one of the following release profile in 950 ml of an pH 6.0        phosphate buffer solution:    -   a. less than about 30% in 35 minutes;    -   b. less than about 60% in 45 minutes; and    -   c. more than 85% in 60 minutes;    -   and wherein said composition upon oral administration in a fed        state exhibits bioequivalence to a commercially available 40 mg        doxycycline composition administered in fasting state and said        bioequivalence is established by:    -   a. a 90% Confidence Interval for mean AUC_((0-t)), which is        between 80% and 125%; and    -   b. a 90% Confidence Interval for mean AUC_((0-inf)), which is        between 80% and 125%.

In another embodiment, the modified release composition of doxycyclineas per present application is used for the treatment of rosacea in humansubjects in need thereof.

In general the primary signs of rosacea are papules, pustules, flushing,persistent redness, visible blood vessels, bumps and pimples.

There are four subtypes of rosacea:

-   -   Subtype 1 (erythematotelangiectatic rosacea), characterized by        flushing and persistent redness, and may also include visible        blood vessels.    -   Subtype 2 (papulopustular rosacea), characterized by persistent        redness with transient bumps and pimples.    -   Subtype 3 (phymatous rosacea), characterized by skin thickening,        often resulting in an enlargement of the nose from excess        tissue, and    -   Subtype 4 (ocular rosacea), characterized by ocular        manifestations such as dry eye, tearing and burning, swollen        eyelids, recurrent styes and potential vision loss from corneal        damage.

In another embodiment, the modified composition of doxycycline as perpresent application is used for treating diseases or conditions in whichcollagenase is produced in excessive amounts causing pathologicaldestruction of tissues, such as periodontal disease, rheumatoidarthritis, hyperparathyroidism, diabetes and acne.

In another embodiment, the present application relates to a method oftreating rosacea in a human subject in need thereof comprising:

-   -   I. doxycycline,    -   II. one or more water soluble and insoluble polymers, and    -   III. one or more pharmaceutically acceptable excipients;    -   wherein said composition has reduced food effect, and said food        effect is less than about 35% in C_(max); and    -   wherein said composition upon oral administration in a fed state        exhibits bioequivalence to a commercially available 40 mg        doxycycline composition administered in fasting state and said        bioequivalence is established by:    -   a. a 90% Confidence Interval for mean AUC_((0-t)), which is        between 80% and 125%; and    -   b. a 90% Confidence Interval for mean AUC_((0-inf)), which is        between 80% and 125%.

In another embodiment, the present application relates to a method oftreating rosacea in a human subject in need thereof comprising:

-   -   I. about 46 mg of doxycycline hyclate,    -   II. one or more water soluble and insoluble polymers, and    -   III. one or more pharmaceutically acceptable excipients;    -   wherein said composition has reduced food effect, and said food        effect is less than about 35% in C_(max); and    -   wherein said composition upon oral administration in a fed state        exhibits bioequivalence to a commercially available 40 mg        doxycycline composition administered in fasting state and said        bioequivalence is established by:    -   c. a 90% Confidence Interval for mean AUC_((0-t)), which is        between 80% and 125%; and    -   d. a 90% Confidence Interval for mean AUC_((0-inf)), which is        between 80% and 125%.

In another embodiment, the modified release composition comprisingdoxycycline has reduced food effect and said food effect is at least 15%lower compared to the food effect of commercially available 40 mgdoxycycline composition in C_(max) and AUC (AUC_((0-t)) and/orAUC_((0-inf)).

In another embodiment, the modified release composition comprisingdoxycycline has reduced food effect and said food effect is at least 20%lower compared to the food effect of commercially available 40 mgdoxycycline composition in C_(max) and AUC (AUC_((0-t)) and/orAUC_((0-inf)).

In another embodiment, the modified release composition comprisingdoxycycline, has reduced food effect and said food effect is at least30% lower compared to the food effect of commercially available 40 mgdoxycycline composition in C_(max) and AUC (AUC_((0-t)) and/orAUC_((0-inf)).

In another embodiment, the modified release composition comprisingdoxycycline has reduced food effect in AUC and said food effect in AUCis at least 40% lower compared to the food effect in AUC of commerciallyavailable 40 mg doxycycline composition in AUC (AUC_((0-t)) and/orAUC_((0-inf))).

In another embodiment, the modified release composition comprisingdoxycycline has reduced food effect in AUC and said food effect in AUCis at least 50% lower compared to the food effect in AUC of commerciallyavailable 40 mg doxycycline composition in AUC (AUC_((0-t)) and/orAUC_((0-inf))).

In another embodiment, the present application relates to a method oftreating rosacea in a human subject in need thereof comprising:

-   -   I. doxycycline;    -   II. one or more water soluble and insoluble polymers; and    -   III. one or more pharmaceutically acceptable excipients;    -   wherein said composition has no food effect established by        following parameters:    -   (a) a 90% Confidence Interval for mean AUC_((0-t)) of the        composition administered under fed state to human subjects is        within 80.00% to 125.00% of a AUC_((0-t)) of the composition        administered to human subjects in a fasting state; and    -   (b) a 90% Confidence Interval for mean AUC_((0-inf)) of the        composition administered under fed state to human subjects is        within 80.00% to 125.00% of a AUC_((0-inf)) of the composition        administered to human subjects in a fasting state.

In another embodiment, the present application relates to a method oftreating rosacea in a human subject in need thereof comprising:

-   -   I. about 46 mg of doxycycline hyclate,    -   II. one or more water soluble and insoluble polymers, and III.        one or more pharmaceutically acceptable excipients;    -   wherein said composition has no food effect established by        following parameters:    -   (a) a 90% Confidence Interval for mean AUC_((0-t)) of the        composition administered under fed state to human subjects is        within 80.00% to 125.00% of a AUC_((0-t)) of the composition        administered to human subjects in a fasting state; and    -   (b) a 90% Confidence Interval for mean AUC_((0-inf)) of the        composition administered under fed state to human subjects is        within 80.00% to 125.00% of a AUC_((0-inf)) of the composition        administered to human subjects in a fasting state.

In another embodiment, the present application relates to a method oftreating rosacea in a human subject in need thereof comprising:

-   -   I. about 46 mg of doxycycline hyclate,    -   II. one or more water soluble and insoluble polymers, and    -   III. one or more pharmaceutically acceptable excipients;    -   wherein said composition has reduced food effect; and    -   wherein said composition upon oral administration in a fasting        state provides at least one of the following pharmacokinetic        parameters:    -   a. doxycycline plasma concentration of not more than about 15        ng/ml of doxycycline at 30 minutes;    -   b. doxycycline plasma concentration of not more than about 60        ng/ml of doxycycline at 45 minutes;    -   c. doxycycline plasma concentration of not more than about 200        ng/ml of doxycycline at 60 minutes; and    -   d. doxycycline plasma concentration from about 200 ng/ml to        about 1000 ng/ml of doxycycline at above 90 minutes..

In another embodiment, the present application relates to a method oftreating or preventing rosacea in a patient known or suspected to be inneed of such treatment or prevention comprising administering to thepatient a modified release composition for once daily oraladministration in a human subject in need thereof comprising

-   -   I. about 46 mg of doxycycline hyclate;    -   II. one or more water soluble and insoluble polymers; and    -   III. one or more pharmaceutically acceptable excipients;    -   wherein said composition has dC/dT value less than about 80% of        the dC/dT value provided by the commercially available 40 mg        doxycycline composition, and said dC/dT is measured in a single        dose human pharmacokinetic study in fasting state and in a time        period of T_(0min) to T_(60mins).

The AUC data from a food-effect study involving administration ofmodified release composition comprising doxycycline of presentapplication under fasting state and fed state (with a high-fat meal)provides exposure to the doxycycline and wherein the exposure ofdoxycycline is not affected by food. Therefore the modified releasecomposition of present application can be taken without regard to meals.

The AUC data from a food-effect study involving administration ofmodified release composition comprising doxycycline of presentapplication under fasting state and fed state (with meal) providesexposure to the doxycycline and wherein the exposure of doxycycline isnot affected by food. Therefore the modified release composition ofpresent application could be taken without regard to meals.

In another embodiment, administration of the modified releasecomposition for once daily oral administration comprising doxycycline tohuman subjects in need thereof of present application may not requireadministration of adequate amounts of fluid along with the saidcomposition to wash down the composition to reduce the risk ofesophageal irritation and ulceration.

In another embodiment, the present application relates to a modifiedrelease composition comprising

-   -   I. about 46 mg of doxycycline hyclate;    -   II. one or more water soluble and insoluble polymers; and    -   III. one or more pharmaceutically acceptable excipients;    -   wherein said composition has dC/dT value less than about 80% of        the dC/dT value provided by the commercially available 40 mg        doxycycline composition, and said dC/dT value is measured in a        single dose human pharmacokinetic study in a fasting state and        in a time period of T_(0min) to T_(60mins).

In some aspects, the modified release composition comprising about 46 mgof doxycycline hyclate has dC/dT value less than about 70% of the dC/dTvalue provided by the commercially available 40 mg doxycyclinecomposition, and said dC/dT value is measured in a single dose humanpharmacokinetic study in a fasting state and in time period of T_(0min)to T_(60mins).

In some aspects, the modified release composition comprising about 46 mgof doxycycline hyclate has dC/dT value less than about 60% of the dC/dTvalue provided by the commercially available 40 mg doxycyclinecomposition, and said dC/dT value is measured in a single dose humanpharmacokinetic study in fasting state and in a time period of T_(0min)to T_(60mins).

In some aspects, the modified release composition for once daily oraladministration in a human subject in need thereof comprising about 46 mgof doxycycline hyclate has dC/dT value less than 50% of the dC/dT valueprovided by the commercially available 40 mg doxycycline composition,and said dC/dT value is measured in a single dose human pharmacokineticstudy in fasting state and in a time period of T_(0min) to T_(60mins).

In some aspects, the modified release composition comprising about 46 mgof doxycycline hyclate has dC/dT value less than about 40% of the dC/dTvalue provided by the commercially available 40 mg doxycyclinecomposition, and said dC/dT value is measured in a single dose humanpharmacokinetic study in fasting state and in a time period of T_(0min)to T_(60mins).

In another embodiment, the modified release composition comprising

-   -   I. about 46 mg of doxycycline hyclate;    -   II. one or more water soluble and insoluble polymers; and    -   III. one or more pharmaceutically acceptable excipients;    -   wherein said composition has dC/dT value less than about 80% of        the dC/dT value provided by the commercially available 40 mg        doxycycline composition, and said dC/dT value is measured in a        single dose human pharmacokinetic study in a fasting state and        in a time period of T_(0min) to T_(60mins); and wherein said        composition has reduced food effect.

In another embodiment, the modified release composition comprising

-   -   I. about 46 mg of doxycycline hyclate;    -   II. one or more water soluble and insoluble polymers; and    -   III. one or more pharmaceutically acceptable excipients;    -   wherein said composition has dC/dT value less than about 80% of        the dC/dT value provided by the commercially available 40 mg        doxycycline composition, and said dC/dT value is measured in a        single dose human pharmacokinetic study in a fasting state and        in a time period of T_(0min) to T_(60mins); and wherein said        composition has reduced food effect, and said food effect is        less than about 35% in C_(max).

In another embodiment, the modified release composition comprising

-   -   I. about 46 mg of doxycycline hyclate;    -   II. one or more water soluble and insoluble polymers; and    -   III. one or more pharmaceutically acceptable excipients;    -   wherein said composition has dC/dT value less than about 80% of        the dC/dT value provided by the commercially available 40 mg        doxycycline composition, and said dC/dT value is measured in a        single dose human pharmacokinetic study in a fasting state and        in a time period of T_(0min) to T_(60min); and wherein said        composition has reduced food effect, and said food effect is        less than about 15% in AUC.

In another embodiment, the modified release composition comprising

-   -   I. about 46 mg of doxycycline hyclate;    -   II. one or more water soluble and insoluble polymers; and    -   III. one or more pharmaceutically acceptable excipients;    -   wherein said composition has dC/dT value less than about 80% of        the dC/dT value provided by the commercially available 40 mg        doxycycline composition, and said dC/dT value is measured in a        single dose human pharmacokinetic study in a fasting state and        in a time period of T_(0min) to T_(60min); and wherein said        composition has reduced food effect, and said food effect is        less than about 12% in AUC_((0-t)).

In another embodiment, the modified release composition comprising

-   -   I. about 46 mg of doxycycline hyclate;    -   II. one or more water soluble and insoluble polymers; and    -   III. one or more pharmaceutically acceptable excipients;    -   wherein said composition has dC/dT value less than about 80% of        the dC/dT value provided by the commercially available 40 mg        doxycycline composition, and said dC/dT value is measured in a        single dose human pharmacokinetic study in a fasting state and        in a time period of T_(0min) to T_(60min); and wherein said        composition has reduced food effect, and said food effect is        less than about 12% in AUC_((0-inf)).

In another embodiment, the modified release composition comprisingdoxycycline, wherein said composition has reduced food effect and saidfood effect in C_(max) is lower than the food effect in C_(max) ofcommercially available 40 mg doxycycline composition by at least 15%.

In another embodiment, the modified release composition comprisingdoxycycline, wherein said composition has reduced food effect and saidfood effect in AUC is lower than the food effect in AUC of commerciallyavailable 40 mg doxycycline composition by at least 15%.

In another embodiment, the modified release composition comprisingdoxycycline, wherein food effect of said composition is at least 15%lower compared to the food effect of commercially available 40 mgdoxycycline composition.

In another embodiment, the present application relates to a modifiedrelease composition comprising

-   -   I. about 46 mg of doxycycline hyclate;    -   II. one or more water soluble and insoluble polymers; and    -   III. one or more pharmaceutically acceptable excipients;    -   wherein said composition has dC/dT value less than 80% of the        dC/dT value provided by the commercially available 40 mg        doxycycline composition, and said dC/dT value is measured in a        single dose human pharmacokinetic study in a fasting state and        in a time period of T_(0min) to T_(60mins);    -   and wherein said composition provides C_(max) from about 200        ng/ml to about 1000 ng/ml.

In another embodiment, the present application relates to a modifiedrelease composition comprising

-   -   I. about 46 mg of doxycycline hyclate;    -   II. one or more water soluble and insoluble polymers; and    -   III. one or more pharmaceutically acceptable excipients;    -   wherein said composition has dC/dT value less than about 80% of        the dC/dT value provided by the commercially available 40 mg        doxycycline composition, and said dC/dT value is measured in a        single dose human pharmacokinetic study in fasting state and in        a time period of T_(0min) to T_(60mins); and    -   wherein said composition provides at least one of the following        pharmacokinetic parameters:    -   a. average input rate of from about 5 ng/hr/ml to about 8        ng/hr/ml during the time period of T_(0min) to T_(30mins).    -   b. average input rate of from about 15 ng/hr/ml to about 20        ng/hr/ml during the time period of T_(0min) to T_(60mins).

In another embodiment, the modified release composition comprising (i)about 46 mg of doxycycline hyclate, (ii) one or more water soluble andinsoluble polymers and (iii) one or more pharmaceutically acceptableexcipients, wherein said composition when administered to a humansubject under fasting state provides average input rate of about 5ng/hr/ml to 8 ng/hr/ml during the time period of T_(0mins) toT_(30 mins).

In another embodiment, the modified release composition comprising (i)about 46 mg of doxycycline hyclate, (ii) one or more water soluble andinsoluble polymers and (iii) one or more pharmaceutically acceptableexcipients, wherein said composition when administered to a humansubject under fasting state provides average input rate of about 15ng/hr/ml to 20 ng/hr/ml during the time period of T_(0min) toT_(60 mins).

In another embodiment, the modified release composition comprising

-   -   I. about 46 mg of doxycycline hyclate;    -   II. one or more water soluble and insoluble polymers; and    -   III. one or more pharmaceutically acceptable excipients;    -   wherein said composition has dC/dT value less than about 80% of        the dC/dT value provided by the commercially available 40 mg        doxycycline composition, and said dC/dT is measured in a single        dose human pharmacokinetic study in a fasting state and in a        time period of T_(0min) to T_(60mins); and    -   wherein said composition upon oral administration in fasting        state exhibits bioequivalence to a commercially available 40 mg        doxycycline composition administered in fasting state and said        bioequivalence is established by:    -   a. a 90% Confidence Interval for mean AUC_((0-t)), which is        between 80% and 125%,    -   b. a 90% Confidence Interval for mean AUC_((0-inf)), which is        between 80% and 125%, and    -   c. a 90% Confidence Interval for mean C_(max), which is between        80% and 125%.

In another embodiment, the modified release composition for once dailyoral administration in a human subject in need thereof comprising

-   -   I. about 46 mg of doxycycline hyclate;    -   II. one or more water soluble and insoluble polymers; and    -   III. one or more pharmaceutically acceptable excipients;    -   wherein said composition has dC/dT value less than about 80% of        the dC/dT value provided by the commercially available 40 mg        doxycycline composition, and said dC/dT is measured in a single        dose human pharmacokinetic study in a fasting state and in a        time period of T_(0min) to T_(60mins); and    -   wherein said composition upon oral administration in a fed state        exhibits bioequivalence to a commercially available 40 mg        doxycycline composition administered in fasting state and said        bioequivalence is established by:    -   a. a 90% Confidence Interval for mean AUC_((0-t)), which is        between 80% and 125%; and    -   b. a 90% Confidence Interval for mean AUC_((0-inf)), which is        between 80% and 125%.

In another embodiment, the modified release composition of the presentapplication is orally administered once daily.

In another embodiment, the modified release composition of the presentapplication is orally administered twice daily.

In another embodiment, the modified release composition of the presentapplication is orally administered to human subjects in need thereof.

In another embodiment, the modified release composition of the presentapplication comprises doxycycline, wherein said doxycyline is an acidaddition salt of doxycycline. In still another aspect of thisembodiment, the doxycycline is administered in an amount of betweenabout 30 and less than 50 mg, based on the weight of doxycycline base,in yet another aspect, between about 35 and about 45 mg, and in yet afurther aspect between about 35 and about 40 mg of doxycycline base onthe weight of doxycycline base.

In another embodiment, the modified release composition of the presentapplication comprises doxycycline, which is doxycycline hyclate.

In another embodiment, doxycycline hyclate is present in an amount ofabout 46 mg.

In another embodiment, doxycycline hyclate is present in an amount of46.16 mg.

In another embodiment, the present application relates to a modifiedrelease composition comprising (i) doxycycline hyclate, (ii) one or morewater soluble and insoluble polymers and (iii) other pharmaceuticallyacceptable excipients.

In another embodiment, the present application relates to a modifiedrelease composition of doxycycline for once daily administration,wherein the said composition comprises of (i) one or more coreconsisting of doxycycline, (ii) a release layer containing one or morewater soluble and insoluble polymers over the core and (iii) one or morepharmaceutically acceptable excipients.

In another embodiment, the present application relates to a modifiedrelease composition of doxycycline for once daily administration,wherein the said composition comprises of core consisting of about15-20% w/w of doxycycline, about 10-18% w/w one or more water solubleand insoluble polymers and 1-20% of pharmaceutically acceptableexcipients, based on the total weight of the final composition.

In another embodiment, the present application relates to a modifiedrelease composition of doxycycline for once daily administration,wherein the said composition comprises of core consisting of about15-20% w/w of doxycycline hyclate, about 10-18% w/w one or more watersoluble and insoluble polymers and 1-20% of pharmaceutically acceptableexcipients, based on the total weight of the said composition.

In another embodiment, the present application relates to a modifiedrelease composition of doxycycline for once daily oral administrationcomprising one or more core comprising of about 15-20% w/w ofdoxycycline hyclate and the core is further coated by release layerconsisting of from about 10-18% w/w one or more water soluble andinsoluble polymers.

In one aspect the release layer release comprises a mixture of at leastone water soluble polymer and at least one water insoluble polymer.

In another aspect, the release layer comprises of from about 5% w/w toabout 40% w/w of water insoluble polymer and from about 2% w/w to 20%w/w of water soluble polymer, based on total weight of the saidcomposition.

In another aspect, the release layer comprises of from about 5% w/w toabout 40% w/w of water insoluble polymer and from about 5% w/w to 15%w/w of water soluble polymer, based on total weight of the saidcomposition.

In another aspect, the release layer release comprises a mixture of atleast one water soluble polymer and at least one water insoluble polymerand wherein the release layer has a thickness of not more than 500 μm.

In an aspect, the water insoluble polymer can be selected from the groupof pH-dependent polymer, hydrophobic polymer, hydrophobic swellablepolymer, hydrophobic non-swellable polymers or mixtures thereof.

Examples of water insoluble polymer includes but not limited to polymethacrylic acid derivatives, cellulose derivatives, acrylic acidderivatives, maleic acid copolymers, polyvinyl derivatives, Cellulosebased pH dependent release retardant polymers includehydroxypropylmethylcellulose acetate succinate,hydroxypropylmethylcellulose phthalate, hydroxymethylethylcellulosephthalate, cellulose acetate phthalate, cellulose acetate succinate,cellulose acetate maleate, cellulose acetate trimelliate cellulosebenzoate phthalate, cellulose propionate phthalate, methylcellulosephthalate, carboxymethylethylcellulose phthalate,ethylhydroxyethylcellulose phthalate and the like, acrylic copolymerbased pH dependent release retardant include styrene, acrylic acidcopolymer, methyl acrylate, acrylic acid copolymer, methyl acrylate,methacrylic acid copolymer, butyl acrylate, methacrylic acid, methylmethacrylate copolymer (e.g. Trade-names: Eudragit L 100 and Eudragit S,available from Rohm Pharma), ethyl acrylate copolymer (e.g. Trade-name:Eudragit L 100-55, available from Rohm Pharma), octyl acrylatecopolymer, Maleic copolymer based pH dependent release retardant includevinylacetate, maleic acid anhydride copolymer, styrene, maleic acidanhydride copolymer, styrene, maleic acid monoester copolymer,vinylmethylether, maleic acid anhydride copolymer, ethylene, maleic acidanhydride copolymer, vinylbutylether, maleic acid anhydride copolymer,acrylonitrile, methyl acrylate, maleic acid anhydride copolymer, butylacrylate, styrene, maleic acid anhydride copolymer and the like,Polyvinyl derivative based pH dependent release retardant includespolyvinyl alcohol phthalate, polyvinylacetal phthalate, polyvinylbutylate phthalate, polyvinylacetoacetal phthalate and the like. Amongthese examples, methacrylic acid, methylmethacrylate copolymer andmethacrylic acid, ethylacrylate copolymer are available under the brandname Eudragit®.

In another aspect, the water soluble polymer can be selected from thegroup of hydrophillic polymer, hydrophillic swellable polymers, orhydrophillic non-swellable polymer or mixtures thereof.

Examples of water soluble polymers include, but not limited to,alkylcelluloses such as methylcellulose; hydroxyalkylcelluloses, forexample, hydroxymethyl cellulose, hydroxypropylmethyl cellulose,hydroxyethyl cellulose, hydroxypropyl cellulose andhydroxybutylcellulose; carboxyalkylcelluloses such ascarboxymethylcellulose; alKali metal salts of carboxyalkylcellulosessuch as sodium carboxymethylcellulose; carboxyalkyl alkylcellulosessuch, carboxyalkylcellulose esters; other natural, semi-synthetic, orsynthetic polysaccharides such as alginic acid, alkali metal andammonium salts thereof, carrageenans, galactomannans, tragacanth,agar-agar, gum arabic, guar gum, xanthan gum, starches, pectins, such assodium carboxymethyl amylopectin, chitin derivates such as chitosan,polyfructans, inulin, sugars, lactose, sucrose, fructose, mannitol,polyvinylalcohol, polyvinylpyrrolidone, polyalkylene oxides such aspolyethylene oxide and polypropylene oxide and copolymers of ethyleneoxide and propylene oxide, and other materials known to one of ordinaryskill in the art.

In another embodiment, the core comprises doxycycline and additionallyone or more pharmaceutically acceptable excipients.

In some aspects, the inert core comprises at least one pharmaceuticallyacceptable excipient selected from the group consisting of: watersoluble, water insoluble, water swellable or water non swellablematerial. For example, the core may comprise one or more of non-pareilseeds, pellets, beads, granules, mini-tablets or a micro-tablet or amicrocapsule, or a millisphere, or a nanocapsule, or a nanosphere, or amicrosphere. The non-pareil seeds may be made up of any pharmaceuticallyacceptable excipients such as starch, sugar, microcrystalline cellulose,inorganic salts like crystal sodium chloride, vegetable gums, waxes, andthe like. The core may be readily available granulated products such asthe spherical granulation product of crystalline cellulose (trade name:AVICEL® SP), the spherical granulation product of crystalline celluloseand lactose (trade name: NONPAREIL® NP-5 and NP-7), the sphericalgranulation product of refined sucrose (trade name: NONPAREIL®-103), andthe spherical granulation product of lactose and alpha-converted starch.The core may also be prepared with the techniques known to a personskilled in the art, such as direct compression, wet granulation, drygranulation, or extrusion-spheronization and the like.

In another embodiment, the active ingredient layer comprisesdoxycycline, one or more hydrophilic polymer, or other pharmaceuticallyacceptable excipients. In certain embodiment, there may be one or morelayers of active ingredients layer comprising doxycycline. The core mayconsist of alternate layers of active ingredient and release layer coat.

In another embodiment, the present application relates to a modifiedrelease composition for once daily oral administration that can beprovided as granules or pellets filled in capsule or sachets or the saidcomposition can be compressed to form a tablet.

In another embodiment, the oral once daily composition of doxycycline asper present application can be provided as granules or pellets which canbe sprinkled on food.

In some aspects, in the pharmaceutical compositions described hereinhaving one or more excipients can perform more than one function. Allexcipients can be used at levels well known to the persons skilled inthe art and within the acceptable limits.

In another embodiment, the modified compositions of doxycycline asdescribed herein may comprise one or more pharmaceutically acceptableexcipients selected from diluent, disintegrant, binder, lubricant,glidant, plasticizer, anti-tacking agent, opacifying agent, and thelike.

Suitable diluents may include one or more of microcrystalline cellulose,starch, dibasic calcium phosphate, tribasic calcium phosphate, calciumcarbonate, dextrose, kaolin, magnesium carbonate, magnesium oxide;sugars such as lactose or sucrose; sugar alcohols such as mannitol,sorbitol or erythritol; or mixtures thereof.

Suitable anti-tacking agents, lubricants or glidants may include one ormore of talc, metallic stearates such as magnesium stearate, calciumstearate, zinc stearate; colloidal silicon dioxide, finely dividedsilicon dioxide, stearic acid, hydrogenated vegetable oil, glycerylpalmitostearate, glyceryl monostearate, glyceryl behenate, polyethyleneglycols, powdered cellulose, starch, sodium stearyl fumarate, sodiumbenzoate, mineral oil, magnesium trisilicate, Kaolin; or mixturesthereof. The anti-tacking agent, lubricant or glidant may be usedinterchangeably.

In one aspect, the compositions of the present application comprisingdoxycycline, wherein said composition is dispensed in HPMC capsules.

In another aspect, the compositions of the present applicationcomprising doxycycline, can be dispensed in capsules containing not morethan 2% w/w of gelatin.

In another embodiment, the present application relates to a modifiedrelease composition for once daily oral administration to a human inneed thereof comprising doxycycline dispensed in HPMC capsules thatyields no more than 1% of hydrolytic impurity such as 4-epidoxycycline,when tested in 45° C. and 75% relative humidity for 24 hrs.

In another embodiment, the present application relates to a process ofpreparing a modified release composition for once daily oraladministration to a human in need thereof comprising the steps of:

-   -   a) preparing doxycline solution comprising of doxycycline, one        or more hydrophilic polymer, or other pharmaceutically        acceptable excipients,    -   b) layering the doxycycline solution of step a) over the inert        cores,    -   c) coating the cores of step b) with one or more water soluble        and insoluble polymers,    -   d) lubricating the coated cores of step c) and    -   e) filling of cores of step d) in capsules or in sachets or        compressing into tablets.

All the layers, i.e. drug layer or the polymer layers, may be applied assolution/dispersion of coating ingredients using any conventionaltechnique known in the art such as spray coating in a conventionalcoating pan or fluidized bed processor or dip coating.

The present application is further illustrated by the examples which areprovided merely to be exemplary of the composition described above anddo not limit the scope of the application. Certain modifications andequivalents will be apparent to those skilled in the art and areintended to be included within the scope of the present application.

EXAMPLES

Examples 1 to Examples 3 illustrates the preparation of doxycyclinehyclate modified release dosage form, equivalent to 40 mg of doxycyclinebase.

Example 1

TABLE 1 Quantity per Unit (%) Ingredients Examples 1 Examples 2 Examples3 Drug Loading Doxycycline Hyclate 16.8 16.8 17.2 Hydroxypropylmethyl-6.5 6.5 6.7 cellulose Sugar Spheres 54.6 54.6 55.9 Polyethylene Glycol400 1.9 1.9 2 Talc 1.9 1.9 2 Purified Water q.s  q.s  q.s ModifiedRelease Coating Methacrcylic acid 10.0 8.19 8.8 Copolymer (Type C)Hypromellose 3 Cps 5 4.0 4.4 (Methocel E3LV) Talc 3 0.3. 2.7. Acetoneq.s. q.s. q.s Water q.s. q.s.  q.s. Lubrication Water q.s. 0.28 0.3Total Weight 100 100 100 Encapsulation Capsule shell size ‘1’ (No.) 1 11

Procedure for manufacturing of doxycycline hyclate modified releasedosage form

A) Preparation of Drug Solution

-   -   Doxycline solution was prepared comprising of doxycycline, one        or more hydrophilic polymer, or other pharmaceutically        acceptable excipients at a temperature above 18° C. and below        18° C.    -   Note: It was found that doxycycline solution if prepared above        18° C. leads to formation of hydrolytic impurity which does not        meet pharmacopoeial acceptable limits.    -   Table 2 shows the impurity levels of formulation prepared in        different conditions.

TABLE 2 Parameter 4-epidoxycycline (%) Cool condition Time Roomtemperature (14° C. ± 4° C.) Initial 0.08 0.03 24 hours 0.19 0.03

B) Drug Layering:

-   -   Drug solution as prepared in step A was layered onto sugar        spheres.

C) Release Layer

-   -   Mixture of methacrylic acid copolymer and hypromellose were        prepared in given solvents to form a mixture, and to this talc        was added and mixed well. This mixture is sprayed onto drug        coated pellets of Step B.

D) Lubrication & Filling

-   -   The pellets of step C were lubricated with talc in blender and        filled in HPMC capsule “size 1”.

Example 4

The in vitro release study for the examples 1, 2 and 3 were carried outin changeover media. It was performed by using USP apparatus I (Basket)with 50 RPM and the dissolution methodology includes change over mediumsi.e., acid stage followed by buffer stage. Table 3 shows dissolutionprofile of example 1, 2, 3 and ORACEA®.

-   -   First the in vitro dissolution was carried out in acid stage        (750 ml of 0.1N HCl solution, USP Type 1 apparatus at a speed of        50 rpm and 37° C.) till 30 minutes. After 30 minutes of in vitro        dissolution of the same composition which is used in acid stage        was carried out in buffer stage (950 ml of phosphate buffer        solution (pH 6.0), USP Type 1 apparatus at a speed of 50 rpm and        37° C.).    -   FIG. 1 shows the in vitro release profile of composition of        examples 1, 2 & 3 carried out in change over media in comparison        with ORACEA®.

TABLE 3 Dissolution profile of examples 1, 2 & 3 (changeover media) Timepoint % Drug release (Minutes) Example 1 Example 2 Example 3 ORACEA ®Acid Stage 30 1 2 3 74 Acid + Buffer stage 30 1 2 3 74 35 3 7 6 74 45 4156 48 76 60 93 93 98 93

Example 5

The in vitro release study for the example 3 was carried out in 950 mlof 0.1N HCl media. It was performed by using USP apparatus I (Basket)with 50 rpm. The dissolution data is given in Table 4.

TABLE 4 Dissolution Data of example 5 (0.1N HCl Media) Time point % Drugrelease 15 mins 1 30 mins 4 45 mins 20 60 mins 49

Example 6

The in vitro release study for the example 3 was carried out in 950 mlof acetate buffer solution (pH 4.5), USP Type 1 apparatus at a speed of50 rpm and 37° C. The dissolution data is given in Table 5.

FIG. 2 shows the in vitro release profile of composition of example 3carried out in acetate buffer solution (pH 4.5) in comparison withORACEA®.

TABLE 5 Dissolution Data of example 6 [acetate buffer solution (pH 4.5)]% drug release Time point Example 1 Example 2 Example 3 ORACEA ®  5 mins0 1 1 19 15 mins 0 1 1 42 30 mins 2 3 4 58 45 mins 21 42 35 65 60 mins72 89 78 68

Example 7

A single center, open-labeled, balanced, randomized, 3-treatment,3-period, 6-sequence, single-dose, crossover, comparative oralbioavailability study was conducted in 52 healthy adult volunteers.

The treatments administered in the study were composition of example 3under the fasting condition (Treatment A), composition of example 3under the fed condition (Treatment B) and ORACEA under the fastingcondition (Treatment C). [ORACEA® (Doxycycline, USP) Capsules 40 mg,capsules of Galderma Laboratories, L.P., USA, Batch No. 1300342A, Expirydate: January 2016]

The subjects were fasted overnight for at least 10 hours beforereceiving a single dose of either composition of example 3 or ORACEA forTreatment A and C.

In Treatment B, the subjects were fasted overnight for at least 10 hoursbefore receiving an FDA-standardized high-fat, high-calorie breakfast(800-1000 kcal) (FDA Guidance 2002), followed by administration of asingle dose of composition of example 3.

A washout period of 7 days was maintained between the dosing ofinvestigational products in consecutive study periods. Blood sampleswere collected to determine the plasma concentrations of doxycyclinebefore dosing (pre-dose) and at 0.5, 0.75, 1, 1.33, 1.67, 2, 2.5, 3,3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 12, 16, 24, 48 and 72 hours after dosing.

The concentrations of doxycycline in plasma were determined by using avalidated LC/MS-MS method.

The pharmacokinetic (PK) parameters C_(max), AUC_(0-t), AUC_(0-inf), %Residual area, T_(lag), T_(max), t_(1/2) and K_(el) were calculatedusing a non-compartmental analysis (NCA) model.

The primary PK parameters, C_(max), AUC_(0-t), AUC_(0-inf) were testedstatistically for the effects of period, treatment, sequence and subjectnested within sequence using the mixed-effect analysis of variance(ANOVA) method.

The geometric least squares means of C_(max), AUC_(0-t), AUC_(0-inf)derived from the ANOVA were compared for bioequivalence under thefasting state and the food-effect and presented in terms of 90%confidence intervals of the test product (composition of example 3) tothe comparator product (ORACEA) ratios.

The comparisons of interest were Treatment A vs. C for thebioequivalence assessment under fasting condition and Treatment B vs Afor the food-effect and Treatment B vs. C.

At the end of the study following parameters are evaluated:

-   -   a. Plasma concentration profile of Doxycyline v. time    -   b. Bioequivalence study v. ORACEA® capsules    -   c. Food effect study and    -   d. dC/dT evaluation

a. Plasma Concentration Profile of Doxycyline v. Time

The plasma concentration of Doxycyline from Example 3 v. time wasplotted for 12 hrs and 72 hrs respectively. FIG. 3 A. shows 12-hour meanplasma doxycycline concentration-time profile and FIG. 3 B. shows72-hour mean plasma doxycycline concentration-time profile of example 3administered to 52 subjects in fasting state.

The plasma concentration of example 3 vis-à-vis ORACEA® for initial timepoint upto 60 minutes is shown Table 6.

TABLE 6 Time points Plasma concentration (ng/ml/hr) (mins) Example 3ORACEA ® 0 0 0 30 6.57 219 45 49.75 344 60 117.03 378

b. Bioequivalence Study v. ORACEA® Capsules

It was observed that the example 3 and ORACEA® 40 mg capsules met thebioequivalence criteria as of 90% confidence intervals of Cmax and AUCparameters were within the acceptance range of 80.00% to 125.00%, infasting conditions.

TABLE 7 Bioequivalence study Treatment A Treatment B Treatment C PKExample 3 Example 3 ORACEA ® Parameters (Fasting) (Fed) 40 mg- FastingC_(max) 473.65 ± 178.79 325.32 ± 75.66  466.40 ± 156.90 AUC_(0-t)6109.48 ± 1703.82 5443.45 ± 1209.17 6239.96 ± 1538.03 AUC_(0-inf)6448.19 ± 1768.20 5780.34 ± 1269.96 6561.49 ± 1602.90 Tlag^(a) (hr)0.495 (0.00-0.999) 2.00 (0.501-3.50) 0.00 (0.00-0.00)  Tmax^(a) (hr) 2.99 (0.745-4.00) 5.49 (2.49-7.00)  1.99 (0.744-4.11) T_(1/2 el) (hr)16.48 ± 3.40  16.50 ± 3.26  16.28 ± 3.87  ^(a)Median (Min-Max)

c. Food Effect Study

The composition of example 3 was evaluated for its food effect vis-à-visORACEA®. The composition of example 3 exhibited a food effect of about31% in C_(max) and further showed reduction of about 31% in food effectwhen compared to food effect of ORACEA®. The results are shown in Table8.

TABLE 8 Food effect The following table lists the food effect values ofcomposition of Example 3 and ORACEA ® Food Effect Reduction of FoodORACEA ® Effect of Example 3 PK Example 3 Example 3 Disclosed comparedto Food Parameters (Fasting) (Fed) Example 3 in label Effect of ORACEA ®(%) Cmax 473.65 325.23 31.31% 45% 30.42% AUC_(0-t) 6109.48 5443.4510.90% 22% 50.45% AUC_(0-inf) 6448.19 5780.34 10.35% 21% 50.71%

d. dC/dT Evaluation

The rate of change of doxycycline plasma concentration during the timeperiod of T_(0mins)-T_(60mins) was tabulated in Table 9. The rate ofchange of doxycycline plasma concentration during the time period ofT_(0min)-T_(60mins) of example 3 was less than 80% of rate of change ofdoxycycline plasma concentration during the time period ofT_(0min)-T_(60mins) of ORACEA®. The rate of change of doxycycline plasmaconcentration during 0-1 hrs of example was 117.03 ng/ml/hr and ORACEA®was 378 ng/ml/hr.

Calculation of dC/dT for example 3:

Plasma Concentration_(T2): 117.303 ng/ml

Plasma Concentration_(T1): 0 ng/ml

Time point₂: 1 hr

-   -   Time point₁: 0 hr

${{dC}\text{/}{dT}} = \frac{\left( {{{Plasma}\mspace{14mu}{Concentration}_{T\; 2}} - {{Plasma}\mspace{14mu}{Concentration}_{T\; 1}}} \right)}{\left( {{{Time}\mspace{14mu}{point}_{2}} - {{Time}\mspace{14mu}{point}_{1}}} \right)}$${{dC}\text{/}{dT}} = \frac{\left( {{11{7.0}3} - 0} \right)}{\left( {1 - 0} \right)}$dC/dT= 117.303  ng/ml /hr

Calculation of dC/dT for ORACEA®:

Plasma Concentration_(T2): 378 ng/ml

Plasma Concentration_(T1): 0 ng/ml

Time point₂: 1 hr

-   -   Time point₁: 0 hr

${{dC}\text{/}{dT}} = \frac{\left( {{{Plasma}\mspace{14mu}{Concentration}_{T\; 2}} - {{Plasma}\mspace{14mu}{Concentration}_{T\; 1}}} \right)}{\left( {{{Time}\mspace{14mu}{point}_{2}} - {{Time}\mspace{14mu}{point}_{1}}} \right)}$${{dC}\text{/}{dT}} = \frac{\left( {378 - 0} \right)}{\left( {1 - 0} \right)}$dC/dT= 378  ng/ml /hr

TABLE 9 dC/dT values: Change in Doxycline concentration as a function oftime Time (Hrs.) Example 3 ORACEA ® 0.0 to 1 117.03 ng/ml/hr 378ng/ml/hr

Although the invention herein has been described with reference toparticular embodiments, it is to be understood that these embodimentsare merely illustrative of the principles and applications of thepresent invention. It is therefore to be understood that numerousmodifications may be made to the illustrative embodiments and that otherarrangements may be devised without departing from the spirit and scopeof the present invention as defined by the appended claims.

1-11. (canceled)
 12. A method of treating inflammatory rosacea or aninflammatory symptom of either rosacea or acne vulgaris comprisingadministering to a human patient in need thereof a modified release oralcomposition comprising: (i) about 30 to less than about 50 mg ofdoxycycline, based on the equivalent weight of doxycycline base, whereinthe doxycycline is in an amount of about 15-20% w/w; (ii) about 10-18%w/w of one or more water soluble and insoluble polymers; and (iii) about1-20% w/w of one or more pharmaceutically acceptable excipients; whereinthe composition is free of any immediate release component; and whereinthe composition provides at least one of the following pharmacokineticparameters: (a) average input rate of about 4 ng/hr/mL to about 15ng/hr/mL during a time period of T₀ min to T₃₀ min, and (b) averageinput rate of about 15 ng/hr/mL to about 40 ng/hr/mL during a timeperiod of T₀ min to T₆₀ min.
 13. The method according to claim 12,wherein the doxycycline is an acid addition salt of doxycycline.
 14. Themethod according to claim 13, wherein the acid addition salt ofdoxycycline is doxycycline hyclate.
 15. The method according to claim14, wherein the doxycycline hyclate is present in an amount of about 46mg.
 16. The method according to claim 12, wherein the compositionexhibits a reduced food effect selected from the group consisting of anAUC of less than about 15% and a C_(max) of less than about 40% uponoral administration to a human.
 17. The method according to claim 16,wherein the composition exhibits a reduced food effect as a C_(max) ofless than about 35% upon oral administration to a human.
 18. The methodaccording to claim 12, wherein the composition provides a reduced foodeffect whereby both AUC and a C_(max) are lower than the food effect ofcommercially available 40 mg doxycycline compositions by at least about15%.
 19. The method according to claim 12, where the composition uponoral administration in a fasting state exhibits bioequivalence to acommercially available 40 mg doxycycline composition and wherein thebioequivalence is established by: (a) a 90% Confidence Interval for meanAUC_((0-t)), which is between 80% and 125%, (b) a 90% ConfidenceInterval for mean AUC_((0-∞)), which is between 80% and 125%, and (c) a90% Confidence Interval for mean C_(max), which is between 80% and 125%.20. The method according to claim 12, wherein the doxycycline is presentin an amount of about 30 to about 45 mg, based on the equivalent weightof doxycycline base.
 21. The method according to claim 12, wherein thedoxycycline is present in an amount of about 35 to about 45 mg, based onthe equivalent weight of doxycycline base.
 22. The method according toclaim 12, wherein the inflammatory symptom of either rosacea or acnevulgaris is papules and pustules of either rosacea or acne vulgaris. 23.The method according to claim 12, for the treatment of inflammatoryrosacea or an inflammatory symptom of rosacea.
 24. The method accordingto claim 12, wherein the composition provides a pharmacokineticparameter of an average input rate of about 5 ng/hr/mL to about 8ng/hr/mL during a time period of T₀ min to T₃₀ min.
 25. The methodaccording to claim 12, wherein the composition provides apharmacokinetic parameter of an average input rate of about 15 ng/hr/mLto about 20 ng/hr/mL during a time period of T₀ min to T₆₀ min.
 26. Themethod according to claim 12, wherein wherein the composition has adC/dT value of less than about 80% of the dC/dT value provided by thecommercially available 40 mg doxycycline composition, measured in asingle dose human pharmacokinetic study in a fasting state and in a timeperiod of T₀ min to T₆₀ mins.
 27. The method according to claim 26,wherein the composition has a dC/dT value of less than about 40% of thedC/dT value provided by the commercially available 40 mg doxycyclinecomposition.